Efficacy, safety, and tolerability of lebrikizumab in adolescent patients with uncontrolled asthma (ACOUSTICS)

Abstract Background Lebrikizumab is a monoclonal antibody that modulates activity of interleukin‐13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard‐of‐care treatment. Methods Adolescents (aged 12–17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%–90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks. Results Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28–0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35–1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21–0.89]; 37.5 mg: 0.42 [95% CI 0.19–0.93]). Treatment‐emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred. Conclusion Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results. Clinical trial registration NCT01875003 (www.ClinicalTrials.gov).

Conclusion: Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results.

K E Y W O R D S
adolescents, IL-13, lebrikizumab, uncontrolled asthma

| INTRODUCTION
Asthma is a heterogeneous disease characterised by chronic inflammation of the airways and is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. 1 Asthma is a global health problem that affects approximately 339 million individuals worldwide. 2 Other published studies reporting on the burden of asthma morbidity in adolescent patients (aged 12-17 years) have indicated that approximately 55%-65% of adolescent patients with severe or difficult-to-treat asthma receive at least three long-term asthma control medications concomitantly. [3][4][5] One study that included 364 adolescent patients with asthma found that, despite treatment, 44% of these patients required a corticosteroid burst and 19% received treatment in an emergency department ≤3 months prior to study baseline. 4 Therefore, patients who have uncontrolled disease despite treatment with high-dose inhaled corticosteroids (ICS) and a second controller represent a population with high unmet medical need. Even with guideline-based asthma therapy, 1 ≤50% of patients have treatmentrefractory or well-controlled asthma. 6 The variable response to standardised therapy may be due to the heterogeneity of asthma. [7][8][9][10] Interleukin (IL)-13 is a pleiotropic type 2 cell cytokine thought to be a key contributor to the pathogenesis of asthma, affecting mucus production, bronchial fibrosis, immunoglobulin E (IgE) production, and smooth-muscle hyperplasia as well as inflammatory-cell recruitment and activation. [11][12][13][14] Lebrikizumab is a monoclonal antibody that binds specifically to IL-13 with very high affinity, prevents the formation of the IL-4Rα/IL-13Rα1 heterodimerisation and downstream signalling, and does not interfere with endogenous regulation of IL-13 activity via IL-13Rα2 binding. [15][16][17] Results from Phase 2 studies showed that treatment with lebrikizumab was associated with improvements in lung function and the rate of asthma exacerbations in patients with uncontrolled asthma, particularly in patients with high periostin levels. 15,18 Replicate Phase 3, randomised, controlled trials (LAVOLTA I/II) were conducted to further assess the efficacy and safety of lebrikizumab in adult patients with uncontrolled asthma despite treatment with standardof-care medications. To help identify those patients hypothesised to most likely benefit from lebrikizumab treatment, they were classified by type 2 biomarker status. However, lebrikizumab did not consistently show statistically significant reductions in asthma exacerbations in biomarker-high adult patients (periostin ≥50 ng/ml, blood eosinophil count ≥300 cells/μl, or both); the primary endpoint was met in LAVOLTA I but not in LAVOLTA II. Although a non-significant numerical trend favouring lebrikizumab was observed, the study sponsor (Roche/Genentech) decided to terminate the lebrikizumab program. 19 ACOUSTICS was a Phase 3 study to investigate the efficacy and safety of lebrikizumab in adolescent patients with uncontrolled asthma despite treatment with standard-of-care medications. The study was prematurely closed by the study sponsor as of July 2016; dosing and further enrolment in ACOUSTICS were closed and all patients were transitioned to safety follow-up. Here, we report the findings from 346 patients (of 375 planned) enrolled in the study.

| Study design and participants
ACOUSTICS was a randomised, multicentre, double-blind, placebocontrolled, parallel-group study that evaluated the efficacy, safety, and tolerability of lebrikizumab in adolescents with asthma whose disease remained uncontrolled despite daily treatment with ICS and at least one additional controller medication (e.g., long-acting β-ag- Information S1 for complete study protocol).
The study consisted of a 2-week screening period (Visits 1-3), a 52-week placebo-controlled period, an active-treatment extension, and a safety follow-up period ( Figure 1). All patients participated in Eligible patients were aged 12-17 years with uncontrolled asthma diagnosed ≥12 months previously, with pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 40%-90% predicted and bronchodilator response of ≥12% and had been receiving background therapy with ICS (500-2000 μg/day fluticasone propionate dry-powder inhaler or equivalent) for ≥6 months. Patients were also required to be receiving at least one additional controller medication (LABAs, LTRAs, LAMAs, or theophylline) for ≥6 months prior to Visit 1 (screening), with no changes within 4 weeks prior to Visit 1 and no anticipated changes throughout the study (except for theophylline dose, which could be adjusted on the basis of theophylline levels).
During the screening period, patients were also assessed for adherence to their current asthma-controller therapy, for their ability to use the equipment necessary for all visits throughout the study, and for complete data in a daily electronic diary (e-Diary) reporting the degree of asthma control provided by their standard-of-care asthma medications. Adherence was defined as affirmative responses from patients that they had taken their asthma-controller therapy on guardians. An independent data monitoring committee reviewed safety data at regular intervals throughout the trial.

| Dose selection, randomisation, and masking
Two dose levels were investigated in the study: the 125-mg dose was expected to demonstrate clinical efficacy while the 37.5-mg dose was selected to ensure minimal overlap in the range of serum exposures between the two doses. Following completion of the screening period F I G U R E 1 Study design schematic. Lebri, lebrikizumab; R, masked randomisation. *After the last dose of study drug during the optional active-treatment extension (or during the placebo-controlled period for patients who opt not to participate in the active-treatment extension), all patients were to be followed-up for safety for 24 weeks. This includes the 4 weeks after the final dose during the placebo-controlled period or the active-treatment extension and a 20-week safety follow-up period SZEFLER ET AL. and after all patient eligibility requirements were confirmed, patients were randomised (at Visit 3) 1:1:1 to receive lebrikizumab 125 mg, lebrikizumab 37.5 mg, or placebo every 4 weeks during the placebocontrolled period. Treatment was initiated on the same day as randomisation (Visit 3, Day 1).
Randomisation was stratified by history of asthma exacerbations within the last 12 months (0, 1-2, or ≥3 events), baseline asthma medications (ICS total daily dose ≥1000 μg of fluticasone propionate dry-powder inhaler or equivalent plus LABA [yes or no]), age group (12-14 or 15-17 years), and country. A dynamic randomisation method was used to obtain an approximate 1:1:1 ratio among the three treatment groups and within each stratum. Patients who opted to transition to the active-treatment extension and who had been assigned to placebo during the placebo-controlled period were rerandomised 1:1 to lebrikizumab 125 mg or 37.5 mg every 4 weeks.
For these patients, randomisation into the active-treatment extension was performed using a block design stratified by age group (12-14 or 15-17 years).

| Procedures
Lebrikizumab 125 mg and 37.5 mg were given subcutaneously every 4 weeks during the placebo-controlled period and the optional active-treatment extension period. Assessments during the study included recording of exacerbation events, healthcare use, spirometry, patient-reported outcome questionnaires, and adverse events.
Pharmacokinetics, pharmacodynamics biomarkers, and antidrug antibodies were measured at Weeks 4, 12, 24, 36, and 52 (see Appendix in Supporting Information S1 for further details). Patients were provided with a handheld peak flow metre and an e-Diary, which were used for once-daily peak expiratory flow measurements and to record use of asthma rescue and controller medication during the study.

| Outcomes
The primary study endpoint was the asthma exacerbation rate over 52 weeks. An asthma exacerbation was defined as new or worsened asthma symptoms that led to treatment with systemic corticosteroids or to hospital admission. Treatment with systemic corticosteroids was defined as oral, intravenous, or intramuscular corticosteroid therapy for ≥3 days or at least one dose of intravenous or intramuscular corticosteroids administered during an emergency department visit. An exploratory endpoint included changes in ACQ-5 score during the placebo-controlled period; because the study was closed prematurely, the remaining exploratory endpoints were not analysed (see Appendix in Supporting Information S1 for study protocol).
The pharmacokinetic objective of the study was to evaluate serum lebrikizumab concentrations over the 52-week placebocontrolled period.
Absolute change from baseline in blood eosinophil count, serum C-C motif chemokine 13 (CCL13), and serum total IgE were measured throughout the 52-week placebo-controlled period as biomarkers of IL-13 activity.

| Statistical analysis
The primary and secondary efficacy analyses were assessed in the intention-to-treat population, in which all randomised patients were grouped by the treatment assigned at randomisation. Per the planned study protocol, hypothesis-testing for the efficacy endpoints was to be performed between each lebrikizumab dose level and the placebo group. To manage the overall type I error, comparison of efficacy in the lebrikizumab 37.5-mg group with that in the placebo group was to be gated on the success of the primary endpoint test in the lebrikizumab 125-mg group compared with the placebo group. Because the study was closed early with no intention of using the results for decision-making purposes, all findings are presented descriptively as point estimates with 95% CIs.
It was estimated that a total of 375 adolescents would be needed to achieve approximately 80% power to detect a 50% reduction in the asthma exacerbation rates with a given lebrikizumab dose level compared with placebo.
The primary efficacy endpoint was the asthma exacerbation rate during the 52-week placebo-controlled period. For each treatment group, the unadjusted asthma exacerbation rate was estimated by the total number of exacerbations observed during the placebocontrolled period divided by the total patient-weeks at risk in the group. For each patient, the period at risk was extended from the day of randomisation to the day of early discontinuation from the placebo-controlled period. Patients who did not experience a protocol-defined asthma exacerbation were censored at the date of the Week 52 visit or at the date of early discontinuation from the study. The mean changes from baseline in prebronchodilator FEV 1 , FENO, AQLQ +12 scores, and asthma rescue medication use were analysed using a mixed-effects repeatedmeasures model. Analysis of the rates of urgent asthma-related healthcare use was performed using Poisson regression with overdispersion similar to that used for protocol-defined asthma exacerbations. Efficacy analyses in this study were also stratified by baseline blood eosinophil levels (≥300 and <300 cells/μl).
Safety analyses were based on all patients who received at least one dose of study drug, with patients grouped by the actual treatment received. Safety was assessed through summary of adverse events, laboratory test results, and incidence of antibodies against lebrikizumab.

| Role of the funding source
The sponsor of the study contributed to study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication. An overview of the secondary and exploratory efficacy endpoints is presented in Table 2. A trend towards increased prebronchodilator    The overall reduction in asthma exacerbation rates in this study was better than those observed in the Phase 3 trials in adults with asthma treated with lebrikizumab: in the LAVOLTA studies, biomarker-high patients (periostin ≥50 ng/ml, blood eosinophil count ≥300 cells/μl, or both) treated with lebrikizumab 125 and 37.5 mg achieved 30% and 51% reductions, respectively (LAVOLTA I), or a 26% reduction (LAVOLTA II; both doses). 19 In ACOUSTICS, adolescent patients in the overall population treated with lebrikizumab 125 and 37.5 mg experienced 51% and 40% reductions in asthma exacerbation rates, respectively, compared with placebo. However, in the high eosinophil group, the ACOUSTICS adolescent patients experienced a 56%-58% reduction in asthma exacerbation rates in contrast to the 39% and 60% in the high eosinophil group in LAVOLTA I and the 32% and 43% reduction in LAVOLTA II.

Beginning
Limitations to this study are associated with premature closing of enrolment and study drug dosing. The results could be influenced by multiple factors that may have reduced the power to detect any differences between treatment groups, including the pattern of early discontinuations (favoured patients in the placebo group) and the decision by the sponsor to close the study prematurely. As such, no statistical analyses beyond point estimates and 95% CIs were performed, limiting the ability to make meaningful comparisons between treatment groups. At the time of study design, which was prior to 2015, the understanding of biomarkers for asthma were unclear.
Therefore, patients with exacerbations in the previous year were not included. Periostin was not measured because these were adolescent patients, and periostin is a bone growth marker which would be elevated and highly variable in adolescents and thus not a good biomarker in this age group. We speculate that 37.5 and 125 mg doses may not be high enough, as a dose response was seen in the atopic dermatitis trials which used much higher doses and increased frequency of dosing. 30 In summary, this study found that treatment with lebrikizumab reduced the exacerbation rates in adolescent patients (greater effect observed with the 125-mg dose than with the 37.5-mg dose) and exacerbation rates were further reduced in patients who have baseline peripheral blood eosinophilia. A unique feature of this trial is that this is the largest free-standing asthma study in adolescent patients. Current asthma trials include adolescents and adults into a single trial, with adolescent patients comprising a small subset of the overall adult population. Lebrikizumab showed a favourable safety profile in adolescents that was consistent with observations from adult studies.  For missing responses, the domain score was calculated using the mean of those questions with an answer present, provided that ≥50% of the questions had an answer present; if <50% of the answers were present, the domain score was set to missing. SZEFLER ET AL.